Tumor and stromal dependence on Hedgehog Pathway signaling 1 Title Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers Authors

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with epithelial-to-mesenchymal transition (EMT) and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradition where it contributes to therapeutic inhibition. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Further, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation and this effect was suppressed by Hh inhibiiton. Our results demonstrate that Gli1 that is upregulated at the tumor-stroma intersection in HNSCC is elevated by radiotherapy where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.